The research object of this proposal is to define the role of the Sonic Hedgehog (SHH) pathway in the biology, pathology, and resistance to chemotherapy of diffuse large B-cell lymphomas (DLBCL), the most common lymphoma worldwide. Although DLBCL is potentially curable wit conventional anthracycline-based therapy, variability in response is often observed and 40-50% patients will relapse and will be not cured with the current available therapies. Our preliminary data provide biological evidence that SHH/GLI signaling pathway plays a role in the pathogenesis of DLBCL. We have also observed high expression of ABCG2, a member of ATP binding cassette family of transporter proteins involved in chemoresistance, in a subset of DLBCL and a positive correlation between expression of ABCG2 and GLI1. Based on these studies, we hypothesize that elevated activity of the SHH signaling pathway promotes DLBCL growth and contributes to chemoresistance in DLBCL. To achieve this aim we will investigate causative factors in the deregulation of SHH/GLI signaling in DLBCL, we will elucidate, in vitro, the biological effect of SHH signaling inhibition using pharmacologic inhibitors as well as silencing the expression of the transducers of the SHH signal, the GLI proteins, and we will uncover the contribution of the SHH signaling in chemoresistance. The effects of inhibiting SHH signaling on lymphoma growth will be also studied in a human DLBCL xenograft model. To investigate the biological role of SHH signaling in DLBCL will provide new insights into the pathogenesis and drug resistance mechanisms of DLBCL, and may contribute to improve the current therapeutic strategies in this lymphoma type. PUBLIC HEALTH RELEVANCE: Diffuse large B-cell lymphoma (DLBC) is the most common aggressive lymphoma worldwide. Understanding the role of Sonic Hedgehog (SHH) pathway in the biology and resistance to chemotherapy in DLBCL will open new avenues for targeted therapy in this lymphoma type.